6&#39;,2-(2&#39;-Arylchromonyl) propionic acids, and analgesic and anti-inflammatory derivatives thereof

ABSTRACT

Propionic acids and their functional derivatives having anti-inflammatory and analgesic properties correspond to the formula ##STR1## in which X is selected from phenyl, halophenyl, polyhalophenyl, lower alkylphenyl, trihalomethylphenyl, aryloxyphenyl, furyl and thienyl and R is selected from hydrogen, lower alkyl, lower omega-hydroxyalkyl, morpholinoethyl and lower dialkylaminoalkyl.

This invention relates to new carboxylic acids which are substituted bya chromonyl group, and more particularly to substituted propionic acids,to functional derivatives thereof, more especially their esters, and tointermediate products used in their preparation, to the methods ofpreparing them, and to their use.

6-(2-Phenylchromonyl) acetic acid is known. The chemical compound wasdescribed by S. Patel and S. Sethna (Journal of the Indian ChemicalSociety, 1973, Volume 50 pages 295-8) its choleretic activity has beenrecently discovered.

New compounds have now been discovered which have remarkable analgesicand anti-inflammatory properties which are only slightly ulcerating.

The propionic acids and their derivatives of the present invention arerepresented by the general formula: ##STR2## in which X is a phenylgroup, a substituted phenyl group, a furyl group or a thienyl group, thesubstituents in the phenyl group being at least one halogen, preferablychlorine a lower alkyl group, preferably methyl, trihalomethyl oraryloxy; and R is hydrogen, a lower alkyl group, a lowerdialkylaminoalkyl group, a lower ω-hydroxyalkyl group, or amorpholinoethyl group.

The addition salts which the basic functional derivatives form withpharmaceutically acceptable acids and the salts with mineral and organicbases of the acids themselves also constitute a feature of thisinvention.

The propionic acids may be prepared from the methyl esters of thecorresponding acetic acids; The methyl ester of a corresponding aceticacid is converted into the corresponding ethyl malonate by treatmentwith ethyl carbonate and sodium hydride. When the interesterificationreaction is complete the alkaline medium enables the carbanion to beobtained, which is then alkylated with methyl iodide indimethylformamide.

Treatment of the alkylation product with a mixture of acetic acid andhydrochloric acid enables the two ester functions to be hydrolysed andthe liberated malonic acid undergoes decarboxylation. The reactionproceeds as follows ##STR3##

The acetic acids which constitute the starting materials form a part ofthe invention and have the general formula: ##STR4## in which X is asdefined above (except when X is a phenyl group). They may be obtaibed byeither of two different routes viz. from 5-methyl-2-hydroxyacetophenoneor from o-hydroxyacetophenone respectively. Each method comprises fivestages, three of which are common to both methods.

METHOD A

5-Methyl-2-hydroxyacetophenone is condensed with an ethyl carboxylate ofthe group X dissolved in a dry aromatic solvent in the presence ofsodium hydride. The dibenzoyl methane thus obtained is cyclised to thecorresponding chromone by treatment with acid.

The 5-methyl group of the original acetophenone is then converted intothe corresponding carboxymethyl group by bromination usingN-bromosuccinimide (NBS), followed by treatment with an alkali metalcyanide, and then hydrolysing with acid, ##STR5##

METHOD B

5-Methoxymethyl-2-hydroxyacetophenone prepared from the correspondingchloromethyl compound is condensed with an ethyl carboxylate of thegroup X in the presence of sodium hydride in a dry aromatic solvent orin dimethyl sulphoxide. The dibenzoylmethane thus obtained is thencyclised with hydrobromic acid to give the correspondingbromomethylchromone, which latter is then treated with an alkali cyanideand then hydrolysed with acid. ##STR6##

In the three reaction diagrams above, X is as previously defined.

The preparation of the esters of the propionic acids may be carried outemploying known methods, more especially by the action of an alcohol ROH(R being a lower alkyl group, a lower ω-hydroxylalkyl group, a lowerdialkylaminoalkyl group or a morpholinoethyl group) upon thecorresponding acid, or that of an alkyl halide upon the sodium orpotassium salt of the acid.

The pharmacological, analgesic and anti-inflammatory effectiveness andthe slightly ulcerating effect of the propionic acids and theirfunctional derivatives was determined by various methods. The compoundsare identified by the numbers of the examples.

The analgesic effect of the compounds of the invention was shown bymeans of the acetic test upon mice (the method of Siegmund as modifiedby Koster, Anderson and Debeer).

In the appended Table I the effective doses ED₅₀ in mg/kg determinedupon some of the compounds tested are given (aspirin was used as acontrol).

                  Table I                                                         ______________________________________                                        Substance       ED.sub.50 in mg/kg                                            ______________________________________                                        Aspirin         130                                                           Example 13      1.5                                                           Example 22      9                                                             Example 25      6                                                             Example 29      2.3                                                           Example 32      4.6                                                           ______________________________________                                    

The anti-inflammatory effect of the compounds claimed was established,inter alia, by the carrageenin-induced oedema test upon rats (Winter etal. -- Proc. Soc. Exp. Biol. Med. 1962, Vol. III, pages 544 and 547).The results obtained with certain of the compounds of the invention aregiven below in Table II (phenylbutazone was used as a control).

                  Table II                                                        ______________________________________                                        Substance    Carrageenin (A.D. 30, mg/kg)                                     ______________________________________                                        Phenylbutazone                                                                             50                                                               Example 13   10                                                               Example 22   65                                                               Example 25   85                                                               Example 29   37                                                               ______________________________________                                    

The compounds were compared with phenylbutazone in order to evaluatetheir ulcerating effect. The method used was that of aggravating ulcerswhich has already been caused in rats by the procedure described by Shayet al (Gastroenterology, 1945, Vol. 5, pages 43 to 61). Table III givesthe results obtained using two preferred compounds of the presentinvention and demonstrates the advantageous character of thesecompounds.

                  Table III                                                       ______________________________________                                                  Aggravation of ulceration                                                       Dose: mg/kg                                                       Substance   body weight/PO   Coefficient                                      ______________________________________                                        Phenylbutazone                                                                            200              100                                              Example 22  300              60                                               Example 13  300              50                                               ______________________________________                                    

Pharmaceutical compositions containing a compound of the invention astheir active ingredient, either in the form of a base or in the form ofthe corresponding organic or mineral salt, may be in the form oftablets, pills, capsules, lozenges, aqueous suspensions, injectablesolutions, sprays, syrups and the like.

The tablets may, if desired, be made resistant to attack by gastricjuices by coating them with a cellulose derivative.

Pharmaceutical compositions comprising a compound of the invention astheir active ingredient and a physiologically acceptable, solid orliquid pharmaceutical excipient or diluent enable the active ingredientto be administered in daily doses of from 20 to 1000 mg. Among theobservations made during clinical trials with the compound of Example 13the following may be mentioned:

Observation 1

Mrs. G -- 60 years old -- Post-fracture gonarthrosis of the left knee.

Treatment with the active ingredient of Example 13 in doses of four 100mg tablets per day for 10 days gave excellent results on the knee, whichreturned to its normal temperature and whose flexion improved from 15 to25°. The analgesic effect was very positive and tolerance was good.

Observation 2

Mr. H -- 21 years old 13 Pseudoarthrosis of the knee.

Treatment with the active ingredient of Example 13 in doses of five 100mg tablets per day for 8 days gave good relief of pain for three hoursand a very good antiinflammatory effect. Tolerance was perfect.

Observation 3

Mrs. F -- 47 years old -- Stripping of varicose veins from the left leg.

Treatment with the active ingredient of Example 13 in doses of six 100mg tablets per day for 5 days gave complete relief, which becameapparent less than 30 minutes after administration and lasted for 3hours. Tolerance was very good.

Observation 4

Mr. R. -- 35 years old -- Sciatica of the radicular type on the rightside.

Treatment with the active ingredient of Example 13 in doses of four 100mg tablets per day for 10 days gave an improvement in the results of theLasegue test from 45 to 75°. The analgesic effect was excellent andtolerance complete.

Observation 5

Mrs. M. -- 48 years old -- Intense cervical pain from an arthriticspine.

A dose of four 100 mg tablets containing the active ingredient ofExample 13 per day for 8 days restored movement to normal amplitude inthe neck unaccompanied by pain. The analgesic effect was good andtolerance was very good.

Among the observations made during clinical trials of the compound ofExample 22 may be mentioned the following five:

Observation 1

Mr. J. -- 79 years old -- Intense pain in the neck and arm on the rightside.

Treatment with four 150 mg tablets containing the active ingredient ofExample 22 per day for eight days gave very good results against painand signs of inflammation. Tolerance was complete.

Observation 2

Mr. S. -- 42 years old -- Very intense lumbar pain.

Treatment with the active ingredient of Example 22 in a dose of four 150mg tablets per day for ten days brought about a very pronouncedimprovement, the distance which the patient could move his fingertipstowards the ground diminishing from 40 to 5 cm. The antalgic effect wasexcellent and tolerance was complete.

Observation 3

Mr. M. -- 62 year old -- Inflammation of the arteries in the lowerlimbs.

Treatment with the active ingredient of Example 22 in a dose of four 150mg tablets per day for five days gives very distinct relief less than 30minutes after administration which relief lasted for more than threehours. Tolerance was satisfactory.

Observation 4

Mr. B. -- 24 years old -- Removal of the left knee-cap.

Treatment with the compound of Example 22 at a dosage of six 150 mgtablets per day for 5 days produced relief which was complete, quick(appearing in less than 30 minutes) and long lasting (longer than 3hours). Tolerance was good.

Observation 5

Mrs. C. -- 56 years old -- lumbar arthrosis with pain in both hips.

The compound of Example 22, taken at the rate of six 150 mg tablets perday for 10 days brought about an appreciable functional improvement andrelief which made its appearance thirty minutes after administration andlasted for three hours. Tolerance was complete.

The following Examples illustrate the preparation of the compounds ofthe present invention.

EXAMPLE 1 6- 2-(4'-Chlorophenyl)chromonyl! acetic acid

This may be prepared by method A by way of the following intermediates:

(a) 2'-Hydroxy-5'-methyl-4"-chlorodibenzoylmethane ##STR7## Empiricalformula C₁₆ H₁₃ ClO₃ : Molecular weight = 288.5

Into a dry reaction vessel are placed 32 g (0.66 mole) of 50% sodiumhydride in mineral oil, 200 ml of anhydrous benzene, and 61.5 g (0.33mole) of ethyl parachlorobenzoate. The mixture is refluxed and over aperiod of three hours a solution of 33.3 g (0.22 mole) of5-methyl-2-hydroxyacetophenone in 100 ml of dry benzene is added drop bydrop. Reflux is continued for three hours after the addition has beencompleted. The reaction mixture is cooled using an ice bath and 50 ml ofethanol is added. The solvents are evaporated under reduced pressureusing an aspirator on a water bath. The pasty residue is dissolved in400 ml of 30% acetic acid for an hour while stirring. The product isfiltered and dried and the dibenzoylmethane obtained is recrystallisedfrom 100 ml of ethanol.

Melting point = 136°-7° Yield = 27.8 g = 44% (Theoretical yield = 63.3g).

(b) 6-Methyl-2-(p-chlorophenyl)chromone ##STR8## Empirical formula C₁₆H₁₁ O₂ Cl: Molecular weight = 270.5

22.5 g (0.095 mole) of the above dibenzoylmethane, 225 ml of glacialacetic acid, and 22.5 ml of concentrated sulphuric acid are placed in aflask. The mixture is refluxed for one hour, cooled and poured into 800ml of iced water. The white solid is filtered, washed with water and atonce recrystallised from alcohol.

Melting point = 190° C Yield 32 15.5g = 73% (Theoretical yield = 21.1 g)

(c) 6-Bromomethyl-2-p-chlorophenylchromone ##STR9## Empirical formulaC₁₆ H₁₀ BrClO₂ : Molecular weight = 361.5

17.5 g (0.065 mole) of 6-methyl-2-(p-chlorophenyl) chromone, 11.6 g(0.065 mole) of N-bromosuccinimide, 700 ml of carbon tetrachloride, and0.1 of g of azobisisobutyronitrile are refluxed for 6 hours whilestirring. The solvents are evaporated and the solid residue isrecrystallised from ethyl acetate.

Melting point = 198° C Yield = 8.8g = 39% (Theoretical yield = 22.75 g)

(d) 6-Cyanomethyl-2-(p-chlorophenyl)chromone ##STR10## Empirical formulaC₁₇ H₁₀ ClNO₂ Molecular weight = 295.71

3.2 g (0.05 mole) of potassium cyanide dissolved in 50 ml of water isplaced in a reaction vessel. The solution is heated to 60° C and asolution of 8.3 g (0.023 mole) of6-bromomethyl-2-(p-chlorophenyl)chromone in 1600 ml of ethanol is addedin four portions, one every 20 minutes. Once the addition is completethe mixture is refluxed for 3 hours, evaporated to dryness and dissolvedin water. The solid is filtered off and recrystallised from alcohol.

Yield = 5 g = 72% (Theoretical yield = 7 g) M.pt. = 213° C

    ______________________________________                                        Analysis                                                                      by weight    Calculated    Found                                              ______________________________________                                        C%           69.03         69.05                                              H%           3.43          3.40                                               N%           4.75          4.73                                               ______________________________________                                    

(e) 6-(2-p-Chlorophenylchromonyl) acetic acid ##STR11## Empiricalformula C₁₇ H₁₁ ClO₄ : Molecular weight = 314.72

A solution of 4.7 g (0.015 mole) of2-(p-chlorophenyl)6-cyanomethylchromone, 10 ml of concentrated sulphuricacid, 10 ml of water, and 10 m of glacial acetic acid is refluxed for 2hours while stirring. The mixture is poured into 60 ml of iced water.The desired acid precipitates. It is purified by formation of its sodiumsalt and recrystallisation from dioxane. It is a white solid. Yield 3 g= 65% M.Pt. = 242° C Theoretical yield = 5.4 g

    ______________________________________                                        Analysis     Calculated    Found                                              ______________________________________                                        C%           64.88         64.85                                              H%           3.52          3.58                                               ______________________________________                                    

EXAMPLE 2 6-(2-o-Chlorophenylchromonyl) acetic acid

This can be prepared by method B utilising the following intermediates:

(a) 2"-Chloro-2'-hydroxymethoxy-5'-methyldibenzoylmethane ##STR12##Empirical formula C₁₇ H₁₅ ClO₄ : Molecular weight = 318.5

This is prepared from 5-methoxymethyl-2-hydroxyacetophenone, which inturn is prepared from 5-chloromethyl-2-hydroxyacetophenone, in thefollowing manner: 1660 g (9 mole) of5-chloromethyl-2-hydroxyacetophenone, 13.5 liters of methanol and 940 mlof concentrated hydrochloric acid are refluxed whilst being stirredvigorously. During two hours 1512 g (27 gr. atoms) of powdered 98% ironis added. Reflux is continued for 11/2 hours and the mixture allowed tostand overnight. The iron is filtered off and the solution concentratedto 5 liters. It is rendered neutral with 1800 g of sodium bicarbonatedissolved in 10 liters of water. The resulting reaction mixture isextracted with 10.5 liters of benzene and the benzene evaporated underreduced pressure. The product is isolated by distillation.

A colourless oil is obtained B.pt. 100° to 103° C/₀.3 mm Yield 1232 g =72% (Theoretical yield = 1620 g)

By operating as described in Example 1a, and using the noted quantities,condensation with ethyl-o-chlorobenzoate is effected: 32 g (0.66 mole)of 50% sodium hydride in mineral oil, 36.5 g (0.20 mole) of ethylo-chlorobenzoate, 23 g (0.13 mole) of2-hydroxymethoxy-5-methylacetophenone, and 225 ml of anhydrous benzene.The dibenzoylmethane is isolated in solution in 30% acetic acid and ispurified by recrystallisation from 200 ml of isopropanol.

A yellow solid is obtained M.pt = 95° C Yield = 26.3 g = 62%(Theoretical yield = 42.5 g)

(b) 6-Bromomethyl-2-(o-chlorophenyl)chromone ##STR13##

Empirical formula C₁₆ H₁₀ Br Cl O₂ : Molecular weight = 349.62

26 g (0.082 mole) of2"-chloro-2'-hydroxy-5'-methoxymethyldibenzoylmethane, 78 ml of 66%hydrobromic acid and 104 ml of glacial acetic acid are refluxed forthree hours. The reaction mixture is poured into iced water and thesolid which separates is filtered. It is then washed with water andrecrystallised from acetone. Yield: 17.4 g = 63% (Theoretical yield =28.5 g). M.pt = 91° C.

    ______________________________________                                        Analysis       Calculated    Found                                            ______________________________________                                        C%             54.97         54.94                                            H%              2.88          2.90                                             Br%           22.86         22.82                                            ______________________________________                                    

(c) 2-(o-Chlorophenyl)-6-cyanomethylchromone ##STR14## Empirical formulaC₁₇ H₁₀ Cl NO₂ : Molecular weight = 295.71

This is prepared by method A, Example 1(d) using the followingmaterials:

5 g (0.0143 mole) of 6-bromomethyl-2-(o-chlorophenyl)chromone, 1.56 g(0.0286 mole) of potassium cyanide, 200 ml of ethanol and 10 ml ofwater. A white solid is obtained which is recrystallised from 50 ml ofethanol. Yield: 3.3 g = 66% (Theoretical yield = 4.3 g) M.Pt 131 to 132°C

    ______________________________________                                        Analysis       Calculated    Found                                            ______________________________________                                        C%             69.05         69.01                                            H%             3.40          3.43                                             M%             4.73          4.77                                              Cl%           11.99         12.03                                            ______________________________________                                    

(d) 6-(2-o-Chlorophenylchromonyl) acetic acid ##STR15## Empiricalformula C₁₇ H₁₁ Cl O₄ : Molecular weight = 314.72

A mixture of 29.5 g (0.1 mole) of2-(o-chlorophenyl)-6-cyanomethylchromone, 68 ml of glacial acetic acidand 68 ml of water is refluxed for three hours. The reaction mixture ispoured into 800 ml of iced water and the solid which separates isfiltered. It is then dissolved in 700 ml of hot 5% sodium bicarbonatesolution, filtered, and acidified with 3N hydrochloric acid. It is thenrecrystallised from ethyl alcohol.

A white solid is obtained. M.pt = 217° to 218° C. Yield 27 g = 90%(Theoretical yield 32 31.4 g)

    ______________________________________                                        Analysis       Calculated    Found                                            ______________________________________                                        C%             64.88         64.90                                            H%             3.52          3.56                                              Cl%           11.27         11.29                                            ______________________________________                                    

EXAMPLE 3 6-(2-m-(Chlorophenyl)chromonyl)acetic acid

This is prepared by the same procedure as that used in Example 2. Thefollowing intermediates are isolated:

(a) 3"-Chloro-2'-hydroxy-5'-methoxymethyldibenzoylmethane ##STR16##Empirical formula C₁₅ H₇ Cl O₄ : Molecular weight = 318.5: A yellowsolid is obtained. M.pt = 86° C: Yield = 44% (b)6-Bromethyl-2-(m-chlorophenyl)-chromone ##STR17## Empirical formula C₁₆H₁₀ Br Cl O₂ : Molecular weight = 349.52 A white solid is obtained. M.pt= 162° C (acetone): Yield = 71% (c)2-(m-Chlorophenyl)-6-cyanomethylchromone ##STR18## Empirical formula C₁₇H₁₀ Cl NO₂ : Molecular weight = 295.71: A white solid is obtained. M.pt= 195°-6° C (ethanol): Yield = 56%.

    ______________________________________                                        Analysis     Calculated    Found                                              ______________________________________                                        C%           69.05         69.02                                              H%           3.40          3.40                                               N%           4.73          4.75                                               ______________________________________                                    

(d) 6-(2-m-Chlorophenylchromonyl) acetic acid ##STR19## Empiricalformula C₁₇ H₁₁ Cl O₄ : Molecular weight = 314.72: A white solid isobtained. M.pt = 208° C (ethanol): Yield 54%.

    ______________________________________                                        Analysis       Calculated    Found                                            ______________________________________                                        C%             64.88         64.85                                            H%             3.53          3.50                                              Cl%           11.27         11.30                                            ______________________________________                                    

EXAMPLE 4 6-(m-Trifluoromethyl-2-phenylchromonyl)acetic acid

This is prepared by Method B. The following intermediates are isolated:

(a) 2'-Hydroxy-5'-methoxymethyl-3"-trifluoromethyldibenzoylmethane##STR20## Empirical formula C₁₈ H₁₄ F₃ O₄ : Molecular weight = 351: Ayellow solid is obtained. M.pt = 128° C (ethanol): Yield = 73%. (b)6-Bromomethyl-2-m-trifluoromethyl-phenylchromone ##STR21## Empiricalformula C₁₇ H₁₀ BrF₃ O₂ : Molecular weight = 383. A beige solid. M.pt =168° C (acetone): Yield = 72%. (c)6-Cyanomethyl-2-trifluoromethylphenylchromone ##STR22## Empiricalformula C₁₈ H₁₀ F₃ NO₂ : Molecular weight = 329: A white solid. M.pt =152° C (ethanol) Yield = 36%. (d)6-(2'-m-Trifluoromethylphenyl)-chromonyl)acetic acid ##STR23## Empiricalformula C₁₈ H₁₁ F₃ O₄ : Molecular weight = 348.29: A white solid. M.pt =195° C (ethanol): Yield: 52%.

    ______________________________________                                        Analysis     Calculated    Found                                              ______________________________________                                        C%           62.08         62.05                                              H%           3.18          3.21                                               F%           16.36         16.39                                              ______________________________________                                    

EXAMPLE 5 6-(2-p-Fluorophenylchromonyl)acetic acid

This is prepared by method B as described in Example 2, with productionof the following intermediates:

(a) 4"-Fluoro-2'-hydroxy-5-methoxymethyldibenzoylmethane ##STR24##Empirical formula C₁₇ H₁₅ FO₄ : Molecular weight = 303. A yellow solid.M.pt = 108° C (di-isopropyl ether). Yield = 50%. (b)5-Bromomethyl-2-(p-fluorophenyl)chromone ##STR25## Empirical formula C₁₆H₁₀ Br FO₂ : Molecular weight = 333.17. A white solid. M.pt = 151° C(acetone): Yield = 45%.

    ______________________________________                                                     Calculated   Found                                               ______________________________________                                        C%             57.68          57.73                                           H%             3.02           3.04                                             Br%           23.09          24.05                                           F%             5.70           5.73                                            ______________________________________                                    

(c) 6-Cyanomethyl-2-p-fluorophenylchromone ##STR26## Empirical formulaC₁₇ H₁₀ NFO₂ : Molecular weight = 279. A white solid. M.pt = 206° C(ethanol). Yield = 54%. (d) 6-(2-p-Fluorophenylchromonyl)acetic acid##STR27## Empirical formula C₁₇ H₁₁ FO₄ : Molecular weight = 298.27. Awhite solid. M.pt = 225° C (ethanol). Yield = 80%.

    ______________________________________                                        Analysis       Calculated    Found                                            ______________________________________                                        C%             68.45         68.48                                            H%             3.71          3.80                                              Tr%           6.37          6.39                                             ______________________________________                                    

EXAMPLE 6 6- 2-(2'-thienyl)chromonyl!acetic acid

Preparation is carried out by the method used in Example 2. Thefollowing intermediates are obtained:

(a)1-(2'-Hydroxy-5'-methoxymethylphenyl)-3-(2"-thienyl)-1,3-dioxopropane##STR28## Empirical formula C₁₅ H₁₄ SO₄. Molecular weight = 290. A whitesolid. M.pt = 90° C (isopropanol). Yield = 50%. (b)6-Bromomethyl-2-(α-thienyl)chromone ##STR29## Empirical formula C₁₄ H₉BrO₂ S. Molecular weight = 321. A white solid. M.pt = 179° C (acetone).Yield = 42%. (c) 6-Cyanomethyl-2-(α-thienyl)chromone ##STR30## Empiricalformula C₁₅ H₉ O₂ NS. Molecular weight = 267.311. A white solid. M.pt =202° C (from ethanol-dioxan 7:3). Yield = 68%. (d) 6-2-(2'-Thienyl)chromonyl!acetic acid ##STR31## Empirical formula C₁₅ H₁₀SO₄. Molecular weight = 286.311. A white solid. M.pt. = 205° C(ethanol). Yield = 73%.

    ______________________________________                                        Analysis       Calculated    Found                                            ______________________________________                                        C%             62.92         62.86                                            H%             3.52          3.59                                              Tr%           11.20         11.23                                            ______________________________________                                    

EXAMPLE 7 6- 2-(2'-furyl)chromonyl!acetic acid

This is prepared by method B used in Example 2. The followingintermediates are obtained:

(a) 1-(2'-Hydroxy-5'-methoxymethylphenyl)-3-(2"-furyl)-1,3-dioxopropane##STR32## Empirical formula C₁₅ H₁₄ O₅. Molecular weight = 274. A yellowsolid. M.pt = 73° C (hexane). Yield = 73%. (b)6-Bromomethyl-2-(2'-furyl)chromone ##STR33## Empirical formula C₁₄ H₉BrO₂. Molecular weight = 289. A white solid. M.pt = 184° C (ethanol).Yield = 56%. (c) 6-Cyanomethyl-2-(2'-furyl)-chromone ##STR34## Empiricalformula C₁₅ H₉ NO₂. Molecular weight = 251. A white solid. M.pt 210° C(ethanol). Yield = 50%. (d) 6- 2-(2'-furyl)chromonyl!acetic acid##STR35## Empirical formula C₁₅ H₁₀ O₅. Molecular weight = 270.25. Awhite solid. M.pt = 198° C (ethanol). Yield = 65%.

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      66.66        66.69                                                    H%      3.73         3.68                                             ______________________________________                                    

EXAMPLE 8 6-(2-Methylchromonyl)acetic acid

This is prepared by the method illustrated in Example 2. The followingintermediates are obtained:

(a) 1-(2'-Hydroxy-5'-methoxymethylphenyl)-1,3-dioxobutane ##STR36##Empirical formula C₁₂ H₁₄ O₄. Molecular weight --. A light yellow solid.M.pt = 89° C (di-isopropylether) Yield = 30%. (b)6-Bromomethyl-2-methylchromone ##STR37## Empirical formula C₁₁ H₉ O₂ Br.Molecular weight = 253. A white solid. M.pt = 132° C (ethanol-water1:1). (c) 6-Cyanomethyl-2-methylchromone ##STR38## Empirical formula C₁₂H₉ O₂ N. Molecular weight = 199. A white solid. M.pt = 122° C(isopropanol). Yield = 53%. (d) 6-(2-Methylchromonyl)acetic acid##STR39## Empirical formula C₁₂ H₁₀ O₄. Molecular weight 218.212. Awhite solid. M.pt = 192° (ethanol). Yield = 51%.

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      66.05        65.99                                                    H%      4.62         4.65                                             ______________________________________                                    

EXAMPLE 9 6- 2-(3'-Thienyl)chromonyl!acetic acid

This is prepared by the method illustrated in Example 2. The followingintermediates were isolated:

(a)1-(2'-Hydroxy-5'-methoxymethylphenyl)-3-(3"-thienyl)-1,3-dioxopropane##STR40## Empirical formula C₁₅ H₁₄ SO₄. Molecular weight = 290. Ayellowish solid, which is not purified but is used in its crude state tomake (b). (b) 6-Bromomethyl-2-(β-thienyl)chromone ##STR41## Empiricalformula C₁₄ H₉ BrO₂ S. Molecular weight 321. A white solid. M.pt = 160°C (ethanol). Yield = 321. (c) 6-Cyanomethyl-2-(β-thienyl)chromone##STR42## Empirical formula C₁₅ H₉ O₂ NS. Molecular weight = 267.319 Awhite solid. M.pt 192° C (washed in ethanol). Yield = 74%. (d) 6-2-(3'-Thienyl)chromonyl!acetic acid ##STR43## Empirical formula C₁₅ H₁₀O₄ S. Molecular weight = 286.311. A white solid. M.pt 207°-8° C(ethanol). Yield = 30%.

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      62.92        62.86                                                    H%      3.52         3.48                                                     S%      11.20        11.18                                            ______________________________________                                    

EXAMPLE 10 6- 2- 2'-(5'-Chlorothienyl!chromonyl!acetic acid

This is prepared as described in Example 2. The following intermediateswere isolated:

(a) 1-(2'-Hydroxy-5'-methoxymethylphenyl)-3-2"-(5"-chlorothienyl)!-1,3-dioxopropane ##STR44## Empirical formula C₁₅H₁₃ O₄ SCl. Molecular weight = 324.5. A solid. M.pt = 106° C(diisopropylether) Yield = 69%. (b) 6-Bromomethyl-2-α-(5'-chlorothienyl)!chromone ##STR45## Empirical formula C₁₄ H₈ Br S ClO₃. Molecular weight = 355.5. A white solid. M.pt = 180° C. Yield 76%.(c) 6-Cyanomethyl-2- 2'-(5'-chlorothienyl)!chromone ##STR46## Empiricalformula C₁₅ H₈ NO₂ S. Molecular weight = 301.5. A white solid. M.pt =210° C (dioxane). Yield = 50%. (d) 6-2'-(5'-Chlorothienyl-2)!chromonyl!acetic acid ##STR47## Empiricalformula C₁₅ H₉ Cl O₄ S. Molecular weight = 320.74. A white solid. M.pt226° to 227° C (dioxane) Yield = 70%.

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      56.17        56.13                                                    H%      2.82         2.99                                                     Cl%     11.06        10.98                                            ______________________________________                                    

EXAMPLE 11 Methyl-6-flavonylacetate ##STR48## Empirical formula C₁₈ H₁₄O₄. Molecular weight = 294.

5.2 g (0.0186 mole) of 6-flavonylacetic acid, 3.7 ml of concentratedsulphuric acid, and 70 ml of anhydrous methanol are refluxed for 7hours. The reaction mixture is poured into 140 ml of iced water. Thedesired ester crystallises. It is filtered, washed with sodiumbicarbonate solution and then with water. Yield = 4,45 g = 81%(Theoretical yield = 5.45 g). M.pt = 117° C (methanol)

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      73.45        73.48                                                    H%      4.79         4.82                                             ______________________________________                                    

EXAMPLE 12 Methyl-6- 2-(2'-thienyl)chromonyl!acetate ##STR49## Empiricalformula C₁₆ H₁₂ SO₄. Molecular weight = 300.32.

30 g (0.105 mole) of 6- 2-(2'-thienyl)chromonyl!acetic acid, 400 ml ofanhydrous methanol and 21 ml of concentrated sulphuric acid are refluxedfor 7 hours. The mixture is cooled and poured into one liter of water.The precipitate obtained is filtered and dried. It is thenrecrystallised from 200 ml of methanol. Yield = 25.8 g = 83%.(Theoretical yield = 31.5 g). M.pt = 106°-7° C.

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      63.99        63.77                                                    H%      4.02         4.28                                                     S%      10.68        10.69                                            ______________________________________                                    

EXAMPLE 13 2- 2'-(α-Thienyl)-6'-chromonyl!propionic acid (a) Ethyl2-(2'- α-thienyl!-6'-chromonyl)-2-methylmalonate ##STR50## Empiricalformula C₂₁ H₂₀ O₆ S. Molecular weight = 400.23.

A suspension of 8.8 g (0.27 mole) of 72% sodium hydride in mineral oilis heated to boiling with 550 ml of ethyl carbonate whilst beingstirred. 73.5 g (0.245 mole) of methyl-6- 2-(α-thienyl)chromonyl!acetate (Example 12) is then added drop by drop. When the addition hasbeen completed, reflux is continued for a further 2 hours. The mixtureis then cooled to 20° C and a solution of 83 g (0.6 mole) of methyliodide in 240 ml of dimethylformamide is quickly added. The reactionmixture is stirred for 12 hours at ambient temperature and the solventsare then evaporated under reduced pressure.

The residue is dissolved in water and extracted with benzene. Theorganic phase is separated, then dried and the benzene evaporated underreduced pressure and the residual oil crystallised from di-isopropylether. Yield = 82%. M.pt = 90° C (di-isopropyl ether).

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      63.00        62.75                                                    H%      5.03         4.95                                                     S%      8.00         7.90                                             ______________________________________                                    

NMR (deuterochloroform), δ (ppm) with reference to tetramethylsilane 6 Hat 1.35 (triplet J = 7 cps), 3 H at 2 (singlet), 4 H at 4.35 (quartet J= 7 cps), 1 H at 6.8 (singlet), 6 H from 7.1 to 8.4 (multiplet).

(b) 2- 2'-(α-Thienyl)-6'-chromonyl!propionic acid ##STR51## Empiricalformula C₁₆ H₁₂ SO₄. Molecular weight = 300.31.

A solution of 80 g (0.2 mole) of ethyl-2-2'-(α-thienyl)-6'-chromonyl!-2-methyl malonate in 400 ml of acetic acidand 200 ml of concentrated hydrochloric acid is refluxed for 7 hours.

The solution is cooled to 10° C and the acid obtained is filtered. It isthen washed with water and purified by being dissolved in hot sodiumbicarbonate solution and refluxing with animal black. The product isfiltered and acidified with concentrated hydrochloric acid. The acid isthen filtered and at once crystallised from acetic acid. A light yellowsolid is obtained. Yield = 75%. M.pt = 255°-260° C.

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      63.98        64.09                                                    H%      4.03         4.03                                                     S%      10.68        10.69                                            ______________________________________                                    

NMR (DMSO d₆ δ (ppm) with reference to tetramethylsilane, 3 H at 1.5(doublet J = 7 cps), 1 H at 3.95 (quartet J = 7 cps), 1 H at 7(singlet), 1 H from 7.25 to 7.50 (multiplet), 2 H from 7.75 to 7.90(multiplet), 2 H from 8 to 8.25 (multiplet), 1 H from 12 to 13 (broadspread).

EXAMPLE 14 2- 2'-(α-furyl)-6'-chromonyl!propionic acid (a) Methyl 6-2-(α-furyl)-chromonyl!acetate ##STR52## Empirical formula C₁₆ H₁₂ O₅.Molecular weight = 284.26.

A solution of 14.4 g (0.053 mole) of 6- 2-(2'-furyl)chromonyl!aceticacid (Example 7) in 200 ml of anhydrous methanol and 12 ml ofconcentrated sulphuric acid is refluxed for 8 hours. The solution isthen cooled and poured into water. The precipitate obtained is filtered,dried and recrystallised. Yield = 70%. M.pt = 117° C (methanol).

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      67.62        67.45                                                    H%      4.25         4.15                                             ______________________________________                                    

(b) Ethyl 2- 6-(2-α-Furylchromonyl)!-2-methylmalonate ##STR53##Empirical formula C₂₁ H₂₀ O₇. Molecular weight = 384.37.

This is prepared as described under (a) of Example 13 from the aboveacetate. A light yellow solid is obtained. Yield = 70%. M.pt = 88° C(di-isopropyl ether).

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      65.62        65.80                                                    H%      5.24         5.15                                             ______________________________________                                    

RMN (deuterochloroform) δ (ppm) with reference to tetramethylsilane, 6 Hat 1.3 (triplet J = 7 cps), 3 H at 2 (singlet), 4 H at 4.3 (quartet J =7 cps), 1 H from 6.55 to 6.7 (multiplet), 1 H at 6.75 (singlet), 5 Hfrom 7.1 to 8.4 (multiplet).

(c) 2- 2'-(α-Furyl)-6'-chromonyl!propionic acid ##STR54##

Empirical formula C₁₆ H₁₂ O₅. Molecular weight = 284.26.

A solution of 5.5 g (0.0143 mole) of ethyl 2-2-(α-furyl)-6-chromonyl!-2-methylmalonate in 28 ml of acetic acid and 14ml of hydrochloric acid is refluxed for 7 hours. Separation andpurification are described under Example 13(b), and a white solid isobtained. Yield = 60%. M.pt = 210°-215° C (isopropanol).

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      67.60        67.57                                                    H%      4.25         4.25                                             ______________________________________                                    

NMR (DMSO d₆ δ (ppm) with reference to tetramethylsilane, 3 H at 1.5(doublet J = 7 cps), 1 H at 4 (quartet J = 7 cps), 1 H at 6.65(singlet), 1 H from 6.8 to 7 (multiplet), 5 H from 7.5 to 8.2(multiplet), 1 H from 12.4 to 13 (spread).

EXAMPLE 15 2- 2'-(β-Thienyl)-6'-chromonyl!propionic acid (a) Methyl2'-(β-Thienyl)-6'-chromonyl!acetate ##STR55## Empirical formula C₁₆ H₁₂O₄ S. Molecular weight = 300.38.

This is prepared as described under Example 14(a). A white solid isobtained. Yield = 93%. M.pt = 111° C.

NMR (deuterochloroform δ (ppm) with reference to tetramethylsilane, 5 Hat 3.8 (singlet), 1 H at 6.8 (singlet), 6 H from 7.4 to 8.3 (multiplet).

(b) Ethyl 2- 2'-(β-Thienyl)-6'-chromonyl!-2-methyl malonate ##STR56##Empirical formula C₂₁ H₂₀ O₆ S. Molecular weight = 400.4.

This is prepared as described under Example 13(a), starting from methyl2'-(β-thienyl)-6'-chromonyl!acetate. A white solid is obtained. Yield =60%. M.pt = 95° C.

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      63.00        62.83                                                    H%      5.03         4.92                                                     S%      8.00         8.10                                             ______________________________________                                    

NMR (deuterochloroform) δ (ppm) with reference to tetramethylsilane, 6 Hat 1.35 (triplet J = 7 cps), 3 H at 2 (singlet), 4 H at 4.4 (quartet J =7 cps), 1 H at 6.8 (singlet), 6 H from 7.3 to 8.5 (multiplet).

(c) 2- 2'-(β-Thienyl)-6'-chromonyl!propionic acid ##STR57## Empiricalformula C₁₆ H₁₂ SO₄. Molecular weight 300.31.

This is prepared as described in Example 13(b) from the correspondingmalonic ester. A light yellow solid is obtained. Yield = 70%. M.pt =215°-218° C.

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      63.98        64.11                                                    H%      4.03         4.12                                                     S%      10.68        10.74                                            ______________________________________                                    

NMR (DMSO d₆) δ (ppm) with reference to tetramethylsilane, 3 H at 1.5(triplet J = 7 cps), 1 H at 3.95 (quartet J = 7 cps), 1 H at 7(singlet), 6 H from 7.65 to 8.65 (multiplet), 1 H from 12.4 to 13(spread).

EXAMPLE 16 2- 2'-(p-Chlorophenyl)-6'-chromonyl!propionic acid (a) Methyl2'-(p-chlorophenyl)-6'-chromonyl!acetate ##STR58## Empirical formula C₁₈H₁₃ ClO₄. Molecular weight = 318.5.

A solution of 105 g (0.344 mole) of 6-2-(p-chlorophenyl)-6'-chromonyl!acetic acid (Example 1) in 1400 ml ofanhydrous methanol and 70 ml of concentrated sulphuric acid is refluxedfor 6 hours. The solution is filtered and allowed to stand overnight at-20° C.

A solid separates and is filtered and is immediately recrystallised from2800 ml of methanol. A white solid is obtained. Yield 85%. M.pt135°-137° C.

(b) Ethyl 2- 2'-(p-Chlorophenyl)-6'-chromonyl!-2-methylmalonate##STR59## Empirical formula C₂₃ H₂₁ ClO₆. Molecular weight 428.872.

A suspension of 3.47 g (0.0725 mole) of 50% sodium hydride in mineraloil in 200 ml of ethyl carbonate is heated to 50° C whilst being stirredand 22 g (0.069 mole) of methyl (2'-p-chlorophenyl-6'-chromonyl)acetateis slowly added thereto. The mixture is then refluxed for 2 hours. It iscooled to ambient temperature and a solution of 23.5 g (0.165 mole) ofmethyl iodide in 68 ml of dimethyl formamide is added drop by drop. Themixture is stirred for 48 hours at 20° C. An abundant precipitateseparates out. The precipitate is filtered off and the mother liquor isevaporated to dryness.

The solid and the dry residue are admixed, washed with water andextracted with benzene. The benzene extract is dried and the solventevaporated under reduced pressure. The yellowish solid residue isrecrystallised from di-isopropyl ether. Yield = 75%. M.pt = 140° C.

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      64.41        64.22                                                    H%      4.93         4.85                                                     Cl%     8.26         8.15                                             ______________________________________                                    

NMR (deuterochloroform) δ (ppm) with reference to tetramethylsilane, 6 Hat 1.3 (triplet J = 7 cps), 3 H at 2 (singlet), 4 H at 4.3 (quartet J =7), 1 H at 6.85 (singlet), 7 H from 7.4 to 8.4 (multiplet).

(c) 2- 2'-(p-Chlorophenyl)-6'-chromonyl!propionic acid ##STR60##Empirical formula C₁₈ H₁₃ O₄ Cl. Molecular weight = 328.737.

A solution of 22 g (0.07 mole) of ethyl 2-2'-(p-chlorophenyl)-6'-chromonyl!-2-methyl malonate in 120 ml of glacialacetic acid and 60 ml of concentrated hydrochloric acid is refluxed for6 hours. The reaction mixture is then poured into water and the solidobtained is filtered. The solid is then dissolved in 1000 ml of a 5%solution of sodium bicarbonate, and the solution is washed with benzene,separated and made acid. Recrystallisation is from isopropanol ortoluene. Yield = 60%. M.pt = 184°-185° C.

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      65.76        65.91                                                    H%      3.99         4.03                                                     Cl%     10.78        10.71                                            ______________________________________                                    

NMR (DMSO d₆) δ (ppm) with reference to tetramethylsilane, 3 H at 1.5(doublet J = 7 cps), 1 H at 3.95 (quartet J = 7 cps), 1 H at 7.1(singlet), 7 H from 7.5 to 8.4 (spread), 1 H from 12.1 to 12.5 (spreadpeaking at 12.3).

EXAMPLE 17 2- 2'-(o-Chlorophenyl)-6'-chromonyl!propionic acid (a) Methyl2'-(o-chlorophenyl)-6'-chromonyl!acetate ##STR61## Empirical formula C₁₈H₁₃ Cl O₄. Molecular weight = 318.5.

This is prepared as described in Example 16(a) from 6- 2-(o-chlorophenylchromonyl!acetic acid (Example 2). An oily product is obtained which isdifficult to crystallise.

NMR (carbon tetrachloride) δ (ppm) with reference to tetramethylsilane,5 H at 3.7 (singlet), 1 H at 6.5 (singlet), 7 H from 7.3 to 8.1(spread).

(b) Ethyl 2- 2'-(o-Chlorophenyl)-6-chromonyl!-2-methyl malonate##STR62## Empirical formula C₂₃ H₂₁ ClO₆. Molecular weight = 428.872.

This is prepared as described in Example 16(b) starting from methyl2'-(o-chlorophenyl)-6'-chromonyl! acetate. The product obtained is ayellow oil which is difficult to crystallise.

NMR (carbon tetrachloride) δ (ppm) with reference to tetramethylsilane,5 H at 1.2 (triplet J = 7 cps), 3 H at 1.9 (singlet), 4 H at 4.2(quartet J = 7 cps), 1 H at 6.55 (singlet), 7 H from 7 to 8.3 (spread).

(c) 2- 2'-(o-Chlorophenyl)-6'-chromonyl!propionic acid ##STR63##Empirical formula C₁₈ H₁₃ O₄ Cl. Molecular weight 328.737.

This is prepared as described in Example 16(c) starting from ethyl 2-2'-(o-chlorophenyl)-6'-chromonyl!-2-methylmalonate. A white solid isobtained. Yield = 60%. M.pt 194°-196° C (toluene).

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      65.76        65.88                                                    H%      3.99         4.07                                                     Cl      10.78        10.62                                            ______________________________________                                    

NMR (DMSO d₆) δ (ppm) with reference to tetramethylsilane, 3 H at 1.55(doublet J = 7 cps), 1 H at 4.05 (quartet J = 7 cps), 1 H at 6.75(singlet), 7 H from 7 to 8.4 (spread), 1 H from 12.5 to 13 (spreadpeaking at 12.75).

EXAMPLE 18 6- 2-(2',4'-Dichlorophenyl)chromonyl!acetic acid (Method B)

This is prepared by method B in the following intermediates:

(a) 2",4"-Dichloro-2'-hydroxy-5'-methoxymethyl dibenzoyl methane##STR64## Empirical formula C₁₇ H₁₄ Cl₂ O₄. Molecular weight = 353.

71.5 g (1.49 mole) of 50% sodium hydride in mineral oil, 600 ml of drybenzene and 15.7 g (0.745 mole) of ethyl 2,4-dichlorobenzoate are placedin a dry reaction vessel.

While stirring, the mixture is refluxed and during a period of two hoursa solution of 89.4 g (0.496 mole) of2-hydroxy-5-methoxymethylacetophenone in 280 ml of dry benzene is addedthereto. The reaction is completed by refluxing for two hours and themixture cooled to 30° C.

300 ml of ethanol is added and the alcohol/benzene azeotrope is removedunder reduced pressure. 2000 ml of 30% acetic acid is added and thewhole extracted with benzene. The benzene extracts are united, thendried and the benzene removed under reduced pressure. The solid residueis recrystallised from 1000 ml of a 9:1 mixture of alcohol and water. Ayellow solid is isolated. Yield = 86%. M.pt = 96°-100° C.

(b) 6-Bromomethyl-2-(2',4'-dichlorophenyl)chromone ##STR65## Empiricalformula C₁₆ H₉ BrCl₂ O₂. Molecular weight = 384.068.

A mixture of 151 g (0.427 mole) of2",4"-dichloro-2'-hydroxy-5'-methoxymethyldibenzoylmethane, 470 ml of62% HBr and 600 ml of glacial acetic acid is heated to 60° to 70° C forthree hours, whilst stirring. The resulting mixture is poured intowater, filtered, and the solid which has separated is recrystallisedfrom a mixture of 1700 ml of acetone and 270 ml of dimethylformamide.Yield = 56%. M.pt = 161° to 162° C (acetone).

    ______________________________________                                        Analysis            Calculated   Found                                        ______________________________________                                                C%      49.96        49.99                                                    H%      2.52         2.65                                                     Cl%     18.43        18.39                                            ______________________________________                                    

(c) 6-Cyanomethyl-2-(2',4'-dichlorophenyl)chromone ##STR66## Empiricalformula C₁₇ H₉ Cl₂ NO₂. Molecular weight = 330.

A solution of 31.2 g (0.48 mole) of 95% potassium cyanide in 250 ml ofwater is heated to 85° C. A solution of 92 g (0.24 mole) of6-bromomethyl-2-(2',4'-dichlorophenyl)chromone in 3900 ml of ethanol isadded in four portions, one every twenty minutes. The mixture isrefluxed for three hours and then evaporated to dryness. The residue isdissolved in 1000 ml of water and filtered. Recrystallisation is theneffected from 2200 ml of a 10:1 mixture of ethanol anddimethylformamide. Yield = 52%. M.pt = 190° C.

NMR (DMSO d₆) δ (ppm) with reference to tetramethylsilane, 2 H at 4.35(singlet), 1 H at 6.80 (singlet), 6 H from 7.4 to 8.7 (spread).

(d) 6- 2-(2',4'-Dichlorophenyl)chromonyl!acetic acid ##STR67## Empiricalformula C₁₇ H₁₀ Cl₂ O₄. Molecular weight = 349.16.

A solution of 10 g (0.03 mole) of6-cyanomethyl-2-(2',4'-dichlorophenyl)chromone in a mixture of 25 ml ofglacial acetic acid, 25 ml of concentrated sulphuric acid, and 25 ml ofwater, is refluxed for 3 hours. The solution is then poured into water,filtered, and the acid dissolved in 500 ml of an aqueous 5% solution ofsodium bicarbonate.

The solution is filtered, acidified, filtered, and the acidrecrystallised from 200 ml of a 12:8 mixture of water and acetic acid.Yield = 62%. M.pt = 213° to 215° C.

    ______________________________________                                        Analysis          Calculated    Found                                         ______________________________________                                         C %              58.47         58.48                                         H %                2.89          2.86                                         Cl %              20.31         20.38                                         ______________________________________                                    

NMR (DMSO d₆) δ (ppm) with reference to tetramethylsilane, 2 H at 3.85(singlet), 1 H at 6.7 (singlet), 6 H from 7.4 to 8.4 (spread), 1 H from1 to 4.5 (spread).

EXAMPLE 19 2- 2'-(2",4"-Dichlorophenyl)-6'-chromonyl!propionic acid (a)Methyl 6- 2-(2',4'-Dichlorophenyl)chromonyl!acetate ##STR68## Empiricalformula C₁₈ H₁₂ Cl₂ O₄. Molecular weight = 363.

A solution of 16.3 g of 6- 2-(2',4'-dichlorophenyl) chromonyl!aceticacid in 200 ml of methanol and 10 ml of concentrated sulphuric acid isrefluxed for six hours. The solution is cooled and the precipitatefiltered. The precipitate is washed with 500 ml of 5% sodium bicarbonateand with water. Yield = 78%. M.pt = 153° C (ethanol).

(b) Ethyl 2- 2'-(2",4"-Dichlorophenyl-6-chromonyl!-2-methyl malonate##STR69## Empirical formula C₂₃ H₂₀ Cl₂ O₆. Molecular weight = 463.317

This is prepared as described in Example 13(a). A white solid isobtained. Yield = 65%. M.pt = 110° C (di-isopropyl ether).

NMR (DMSO d₆) δ (ppm) with reference to tetramethylsilane, 6 H at 1.3(triplet J = 7 cps), 3 H at 2 (singlet), 4 H at 4.3 (quartet J = 7 cps),1 H at 6.7 (singlet), 6 H from 7.3 to 8.4 (spread).

(c) 2- 2'-(2",4"-Dichlorophenyl)-6'-chromonyl!propionic acid ##STR70##Empirical formula C₁₈ H₁₂ Cl₂ O₄. M.pt = 363.19.

This is prepared as described in Example 13(b) from ethyl 2-2'-(2",4"-dichlorophenyl)-6'-chromonyl!-2-methylmalonate. It is a whitesolid. Yield = 60%. M.pt. 194°-195° C (toluene)

    ______________________________________                                        Analysis          Calculated    Found                                         ______________________________________                                        0 %               59.52         59.61                                         H %                3.33          3.30                                         Cl %              19.52         19.48                                         ______________________________________                                    

NMR (DMSO d₆) δ (ppm) with reference to tetramethylsilane, 3 H at 1.5(doublet J = 7 cps), 1 H at 3.95 (quartet J = 7 cps), 1 H spread from 3to 4, 1 H at 6.65 (singlet), 6 H from 7 to 8.4 (spread).

EXAMPLE 20 6- 2-(p-Methylphenyl)chromonyl!acetic acid (Method B)

This is prepared as described in Example 18 making use of the followingintermediates:

(a) 2'-Hydroxy-4"-methyl-5'-methoxymethyldibenzoylmethane ##STR71##Empirical formula C₁₈ H₁₈ O₄. Molecular weight = 298.

The procedure is that described in Example 18(a) A yellow solid isobtained. Yield = 58%. M.pt = 87° to 88° C (di-isopropyl ether).

(b) 2-(4'-Methylphenyl)-6-bromomethylchromone ##STR72## Empiricalformula C₁₇ H₁₃ Br O₂. Molecular weight = 329.

The procedure is that described in Example 18(b) using the abovedibenzoylmethane. A white solid is obtained. Yield = 60%. M.pt = 197° C(acetone + dimethylformamide).

(c) 2-(4'-Methylphenyl)-6-cyanomethylchromone ##STR73## Empiricalformula C₁₈ H₁₃ N O₂. Molecular weight = 275.

By proceeding as described in Example 18(c) using the abovebromomethylchromone. A white solid is obtained. Yield = 62%. M.pt = 197°C (Water + ethanol + dimethylformamide).

NMR (DMSO d₆) δ(ppm) with reference to tetramethylsilane, 3 H at 2.4(singlet), 2 H at 4.25 (singlet), 1 H at 7 (singlet), 7 H from 7.2 to8.3 (spread).

(d) 6- 2-(p-Methylphenyl)chromonyl!acetic acid ##STR74## Empiricalformula C₁₈ H₁₄ O₄. Molecular weight = 294.

After proceeding as described in Example 18(d) using the abovecyanomethylchromone. A white solid is obtained. Yield = 94%. M.pt = 226°to 228° C.

    ______________________________________                                        Analysis          Calculated    Found                                         ______________________________________                                        C %               73.45         73.22                                         H %                4.79          4.70                                         ______________________________________                                    

NMR (DMSO d₆) δ(ppm) with reference to tetramethylsilane, 3 H at 2.4(singlet), 2 H at 3.85 (singlet), 1 H at 7 (singlet), 7 H from 7.2 to8.4 (spread), 1 H from 11.7 to 13.3 (broad spread).

EXAMPLE 21 2- 2'-(p-Methylphenyl)-6-chromonyl!propionic acid (a) Methyl6- 2-(p-methylphenyl)chromonyl!acetate ##STR75## Empirical formula C₁₉H₁₆ O₄. Molecular weight = 308.

This is prepared as described in Example 19(a). A white solid isobtained. Yield = 75%. M.pt = 145° C (methanol).

Ethyl 2- 6'-(2'-p-methylphenylchromonyl)!-2-methylmalonate ##STR76##Empirical formula C₂₄ H₂₄ O₆. Molecular weight = 408.43.

After proceeding as described in Example 19(b) using the above acetate alight yellow solid is obtained. Yield = 58%. M.pt = 132° C.

NMR (deuterochloroform) δ(ppm) with reference to tetramethylsilane, 6 Hat 1.3 (triplet J = 7 cps), 3 H at 2 (singlet), 3 H at 2.45 (singlet), 4H at 4.3 (quartet 8 = 7 cps), 1 H at 6.8 (singlet), 7 H from 7.2 to 8.4(spread).

2- 6'-(2'-p-methylphenyl)chromonyl!propionic acid ##STR77## Empiricalformula C₁₉ H₁₆ O₄. Molecular weight = 308.32.

After proceeding as described in Example 19(c) using the above malonatea white solid is obtained. Yield = 58%. M.pt = 196° to 198° C. AnalysisCalculated Found C% 74.01 73.87 H% 5.23 5.26

NMR (DMSO d₆) δ (ppm) with reference to tetramethylsilane, 3 H at 1.55(doublet J = 7 cps), 3 H at 2.40 (singlet), 1 H at 3.95 (quartet J = 7cps), 1 H at 7 (singlet), 7 H from 7.2 to 8.4 (spread).

EXAMPLE 22 2-(6'-flavonyl)propionic acid (a) Ethyl2-(6'-flavonyl)-2-methylmalonate ##STR78## Empirical formula C₂₃ H₂₂ O₆.Molecular weight = 394.41.

After proceeding as described in Example 13 using methyl-6-flavonylacetate, as starting material a white substance is obtained. Yield =84%. M.pt = 99° to 100° C (di-isopropylether).

NMR (deuterochloroform) δ (ppm) relative to tetramethylsilane, 6 H at0.9 (triplet J = 7 cps), 3 H at 1.6 (singlet), 4 H at 3.9 (quartet J = 7cps), 1 H at 6.4 (singlet), 8 H from 7.2 to 8.1 (multiplet).

(b) 2-(6'-Flavonyl)propionic acid ##STR79## Empirical formula C₁₈ H₁₄O₄. Molecular weight = 294.29

By proceeding as described in Example 13(b) starting with the abovemalonate a white solid is obtained. Yield = 80%. M.pt = 228° C (aceticacid).

    ______________________________________                                        Analysis          Calculated    Found                                         ______________________________________                                        C %               73.46         73.36                                         H %                4.79          4.92                                         ______________________________________                                    

NMR (DMSO d₆) δ (ppm) with reference to tetramethylsilane, 3 H at 1.6(doublet J = 7 cps), 2 H from 3.5 to 4.4 (quartet J = 7 cps on thespread), 1 H at 7.1 (singlet), 8 H from 7.4 to 8.4 (multiplet).

EXAMPLE 23 The acid oxalate of β-diethylaminoethyl 2-(6'-flavonyl)propionate ##STR80##

2.95 g (0.01 mole) of 6-flavonylpropionic acid is dissolved in 200 ml ofalcohol and to it there is added drop by drop a solution of 0.56 g (0.01mole) of potassium dissolved in alcohol. The alcohol is evaporated underreduced pressure and the residue dissolved in 50 ml of acetone. 1.35 g(0.01 mole) of β-chlorotriethylamine dissolved in 4 ml of acetone isthen added. The mixture is refluxed for 3 hours and the acetoneevaporated. The pasty residue is dissolved in chloroform and water. Theorganic phase is separated, washed with 5% sodium bicarbonate solutionand water, then dried over sodium sulphate and the solvents evaporated.The oily residue is dissolved in 50 ml of ethanol and salified withoxalic acid. A white solid is obtained in a yield of 70%. M.pt = 150° to153° C (ethanol)

    ______________________________________                                        Analysis          Calculated    Found                                         ______________________________________                                        C %               63.69         63.68                                         H %                6.20          6.15                                         N %                2.97          3.03                                         ______________________________________                                    

EXAMPLE 24 Ethyl 2-(2'-phenyl-6'-chromonyl)propionate ##STR81##Empirical formula C₂₀ H₁₈ O₄. Molecular weight = 322.34.

A mixture of 20 g (0.68 mole) of 2-(6'-flavonyl) propionic acid, 28 mlof concentrated sulphuric acid and 1000 ml of anhydrous ethanol isrefluxed for seven hours. The mixture is then poured into water andextracted a number of times with ether. The combined ethereal extractsare washed with 5% sodium bicarbonate solution dried and evaporated todryness. The residual oil crystallises. Yield = 98%. M.pt = 74° to 76° C(di-isopropyl ether).

    ______________________________________                                        Analysis          Calculated    Found                                         ______________________________________                                        0 %               74.52         74.35                                         H %                5.63          5.75                                         ______________________________________                                    

EXAMPLE 25 Propyl 2-(2'-phenyl-6'-chromonyl)propionate ##STR82##Empirical formula C₂₁ H₂₀ O₄. Molecular weight = 326.37.

This is prepared as described in Example 24 by esterification of2-(6'-flavonyl)propionic acid with n-propanol. Yield = 55%. Meltingpoint = 59° to 61° C (hexane). Analysis Calculated Found C% 74.98 75.26H% 6.00 5.89

EXAMPLE 26 Isopropyl 2-(2'-phenyl-6'-chromonyl)propionate ##STR83##Empirical formula C₂₁ H₂₀ O₄. Molecular weight = 336.37.

This is prepared as described in Example 24 by esterification of2-(6'-flavonyl)propionic acid with isopropanol. Yield = 80%. M.pt = 78°to 80° C (diisopropyl ether).

    ______________________________________                                        Analysis          Calculated    Found                                         ______________________________________                                        C %               74.98         74.64                                         H %                6.00          5.97                                         ______________________________________                                    

EXAMPLE 27 Butyl 2-(2'-phenyl-6'-chromonyl)propionate ##STR84##Empirical formula C₂₂ H₂₂ O₄. Molecular weight = 350.40.

By proceeding as described in Example 24, a white substance is obtained.Yield = 80%. M.pt = 44° to 46° C (hexane).

    ______________________________________                                        Analysis          Calculated    Found                                         ______________________________________                                        C %               75.40         75.22                                         H %                6.33          6.35                                         ______________________________________                                    

EXAMPLE 28 β-Hydroxyethyl 2-(2'-phenyl-6'-chromonyl)propionatemonohydrate ##STR85## Empirical formula C₂₀ H₂₀ O₆. Molecular weight =356.36.

A mixture of 11.8 g (0.04 mole) of 2-(6'-flavonyl) propionic acid, 100ml of benzene, 100 ml of ethylene glycol, and 1.35 g of p-toluenesulphonic acid is refluxed for four hours in a flask fitted with a Deanand Stark apparatus. The reaction mixture is then poured into water. Anoil separates, is decanted and crystallises yielding a white substance.Yield = 90%. M.pt = 79°-83° C (10 : 6 mixture of hexane and ethylacetate).

    ______________________________________                                        Analysis   Calculated    Found                                                ______________________________________                                        C %        67.40         67.22                                                H %         5.66          5.52                                                ______________________________________                                    

EXAMPLE 29 Methyl 2- 2'-(α-thienyl)-6'-chromonyl!propionate ##STR86##Empirical formula C₁₇ H₁₄ SO₄. Molecular weight = 314.34.

This is prepared as described in Example 24 by esterification, in thepresence of sulphuric acid, of the acid of Example 13 with methanol.Yield = 80%. M.pt = 96° to 98° C (ethyl acetate).

    ______________________________________                                        Analysis   Calculated    Found                                                ______________________________________                                        C %        64.96         65.24                                                H %         4.49          4.27                                                S %        10.20         10.28                                                ______________________________________                                    

EXAMPLE 30 Methyl 2- 2'-(β-thienyl)-6'-chromonyl!propionate ##STR87##Empirical formula C₁₇ H₁₄ SO₄. Molecular weight = 314.34.

This is prepared as described in Example 24 by the esterification, inthe presence of sulphuric acid, of the acid of Example 15 with methanol.Yield = 85%. M.pt = 95° to 98° C (di-isopropyl ether)

    ______________________________________                                        Analysis   Calculated    Found                                                ______________________________________                                        C %        64.95         65.10                                                H %         4.49          4.47                                                S %        10.20         10.20                                                ______________________________________                                    

EXAMPLE 31 Propyl 2-(2'-α-thienyl-6'-chromonyl)propionate ##STR88##Empirical formula C₁₉ H₁₈ O₄ S. Molecular weight = 342.33.

This is prepared as described in Example 25 from the acid of Example 13.A white solid is obtained. Yield = 90%. M.pt = 48° to 52° C.

    ______________________________________                                        Analysis   Calculated    Found                                                ______________________________________                                        C %         66.66        66.47                                                H %         5.29          5.27                                                S %         9.36          9.40                                                ______________________________________                                    

EXAMPLE 32 The acid oxalate of β-morpholinoethyl-2-2'-(α-thienyl)-6'-chromonyl!propionate ##STR89## C24H₂₅ NO₉ S. Molecularweight = 503.5.

A mixture of 12 g (0.04 mole) of 2-2'-(α-thienyl)-6'-chromonyl!propionic acid, 2.55 g (0.04 mole) ofpotassium, and 500 ml of methanol is refluxed for 30 minutes. Thesolvent is evaporated to dryness under reduced pressure and the powderyresidue is dissolved in 50 ml of methyl isobutyl ketone and 10.5 g offreshly distilled chloroethylmorpholine. The mixture is refluxed for 8hours and the solids filtered.

The methyl isobutyl ketone is evaporated from the organic phase underreduced pressure and the oily residue immediately salified with oxalicacid dissolved in acetone. The salt obtained is purified byrecrystallisation from a 6 : 1 mixture of acetone and water. Yield: =70%. M.pt = 167° to 170° C (ethanol).

    ______________________________________                                        Analysis   Calculated    Found                                                ______________________________________                                        C %        57.25         57.27                                                H %        5.00          4.97                                                 N %        2.78          2.71                                                 S %        6.36          6.01                                                 ______________________________________                                    

EXAMPLE 33 6- 2-(2'-phenoxyphenyl)-chromonyl!acetic acid (Method B)

This is prepared as described in Example 18 through the followingintermediates:

(a) 2'-Hydroxy-2"-phenoxy-5'-methoxymethyldibenzoylmethane ##STR90##Empirical formula C₂₃ H₂₀ O₅. Molecular weight = 376.39.

After proceeding as described in Example 18(a), a yellow solid isobtained. Yield = 75%. M.pt = 94° C (di-isopropyl ether).

(b) 2-(2'-Phenoxyphenyl)-6-bromomethylchromone ##STR91## Empiricalformula C₂₂ H₁₅ BrO₃. Molecular weight = 407.25

After proceeding as described in Example 18(b), a white solid isobtained. Yield = 71%. M.pt = 145° C (acetone).

(c) 2-(2'-Phenoxyphenyl)-6-cyanomethylchromone ##STR92## Empiricalformula C₂₃ H₁₅ NO₃. Molecular weight = 353.35

After proceeding as described in Example 18(c), a white solid isobtained. Yield = 38%. M.pt = 138° C (ethanol).

(d) 6- 2-(2'-Phenoxyphenyl)chromonyl!acetic acid ##STR93## Empiricalformula C₂₃ H₁₆ O₅. Molecular weight = 372.36.

After proceeding as described in Example 18(d), a white solid isobtained. Yield = 63%. M.pt = 17° C. (ethanol).

NMR (deuterochloroform) δ (ppm) with reference to tetramethylsilane, 2 Hat 3.8 (singlet), 1 H from 5.2 to 5.5 (broad spread), 13 H from 6.9 to8.3 (spread).

EXAMPLE 34 2- 2'-(2"-Phenoxyphenyl)-6'-chromonyl!propionic acid (a)Methyl 6- 2-(2'-phenoxyphenyl)chromonyl!acetate ##STR94## Empiricalformula C₂₄ H₁₈ O₅. Molecular weight = 386.38.

This is prepared as described in Example 19(a). A white solid isobtained. Yield = 65%. M.pt = 125° C (methanol).

(b) Ethyl 2- 2'-(2"-phenoxyphenyl)-6'-chromonyl!-2-methyl malonate##STR95## Empirical formula C₂₉ H₂₆ O₇. Molecular weight = 486.50

This is prepared as described in Example 19(b). A brown oil which cannotbe crystallised is obtained. Yield = 58%.

NMR (deuterochloroform) δ (ppm) with reference to tetramethylsilane, 6 Hat 1.3 (triplet J = 7 cps), 3 H at 1.9 (singlet), 4 H at 4.2 (quartet J= 7 cps), 13 H from 6.8 to 8.1 (spread),

(c) 2- 2'-(2"-Phenoxyphenyl)-6'-chromonyl!propionic acid ##STR96##Empirical formula C₂₄ H₁₈ O₅. Molecular weight = 386.38.

After proceeding as described in Example 19(c), a white solid isobtained. Yield = 50% M.pt = 175° to 178° C (isopropanol) NMR (DMSO d₆)δ (ppm) with reference to tetramethylsilane, 3 H at 1.55 (doublet J = 7cps), 2 H from 3.8 to 4.2 (quadruplet J = 7 cps spread), 13 H from 6.9to 8.2 (spread).

    ______________________________________                                        Analysis   Calculated    Found                                                ______________________________________                                        C %        74.60         74.35                                                H %         4.69          4.51                                                ______________________________________                                    

EXAMPLE 35 2- 2'-(3"-Trifluoromethylphenyl)-6'-chromonyl!propionic acid(a) Methyl 2-(3'-trifluoromethylphenyl)-6-chromonyl!acetate ##STR97##Empirical formula C₁₉ H₁₃ F₃ O₄. Molecular weight = 361.

This is prepared as described in Example 19(a) by esterification, in thepresence of sulphuric acid, of6-(2-m-trifluoromethylphenylchromonyl)acetic acid. Yield = 83%. M.pt =140° C (methanol).

NMR (DMSO d₆) δ (ppm) relative to tetramethylsilane, 3 H at 3.30(singlet), 2 H at 3.40 (singlet), 1 H at 6.65 (singlet), 7 H from 7.20to 8.00 (multiplet).

(b) Ethyl 2-2'-(3"-trifluoromethylphenyl)-6'-chromonyl!-2-methylmalonate ##STR98##Empirical formula C₂₄ H₂₁ F₃ O₆. Molecular weight = 462.41.

This is prepared as described in Example 19(b). A white solid isobtained. Yield = 64%. M.pt = 82° to 83° C (di-isopropyl ether).

NMR (carbon tetrachloride) δ (ppm) with reference to tetramethylsilane,6 H at 1.3 (triplet J = 7 cps), 3 H at 1.9 (singlet), 4 H at 4.2(quartet J = 7 cps), 1 H at 6.8 (singlet), 7 H from 7.3 to 8.3(multiplet).

(c) 2- 2'-(3"-Trifluoromethylphenyl)-6'-chromonyl!propionic acid##STR99## Empirical formula C₁₉ H₁₃ O₄ F₃. Molecular weight = 362.19

After proceeding as described in Example 19(c), a white solid isobtained. Yield = 60%. M.pt 171° to 173° C (toluene).

    ______________________________________                                        Analysis   Calculated    Found                                                ______________________________________                                        C %        63.00         63.16                                                H %         3.62          3.56                                                F %        15.74         15.82                                                ______________________________________                                    

NMR (DMSO d₆) δ (ppm) with reference to tetramethylsilane, 3 H at 1.6(doublet J = 7 cps), 2 H from 3.4 to 4.4 (quartet J = 7 cps), 1 H at 7.3(singlet), 7 H from 7.8 to 8.6 (multiplet).

We claim:
 1. A carboxychromonyl compound having the formula ##STR100##in which X is selected from the group consisting of phenyl, halophenyl,polyhalophenyl, lower alkylphenyl, and trihalomethylphenyl; and R isselected from the group consisting of hydrogen, lower alkyl, loweromega-hydroxyalkyl, morpholinoethyl and lower dialkylaminoalkyl,together with (a) salts of said compound with pharmaceuticallyacceptable acids when R is morpholinoethyl and lower dialkylaminoalkyland (b) salts of said compound with pharmaceutically acceptable mineraland organic bases when R is hydrogen.
 2. A compound in accordance withclaim 1 wherein R is hydrogen, lower alkyl or lower omega-hydroxyalkyl.3. A carboxychromonyl compound having the formula: ##STR101## in which Xis phenyl and R is hydrogen, lower alkyl or lower omega-hydroxyalkyl,lower dialkylaminoalkyl, together with (a) salts of said compound withpharmaceutically acceptable acids when R is a lower dialkylaminoalkyland (b) salts of said compound with pharmaceutically acceptable mineraland organic bases when R is hydrogen.
 4. A carboxychromonyl compoundhaving the formula: ##STR102## in which X is phenyl and R is hydrogen,lower alkyl or lower omega-hydroxyalkyl; or a pharmaceuticallyacceptable salt thereof.
 5. A compound in accordance with claim 4selected from the group consisting of 2-(6-flavonyl)-propionic acid, andpropyl-2-(2'-phenyl-6'-chromonyl) propionate.
 6. The compound of claim 4which is 2-(6-flavonyl)-propionic acid.
 7. The compound which is2-(6-flavonyl)-propionic acid or a pharmaceutically acceptable salt orester thereof.
 8. An analgesic and anti-inflammatory pharmaceuticalcomposition which comprises (a) the carboxychromonyl compound claimed inclaim 4 in an amount sufficient to provide analgesic andanti-inflammatory activity together with (b) a pharmaceuticallyacceptable diluent therefor.
 9. The composition of claim 8 in the formof tablets.
 10. An analgesic and anti-inflammatory pharmaceuticalcomposition which comprises (a) 2-(6-flavonyl) propionic acid in anamount sufficient to provide analgesic and anti-inflammatory activity,together with (b) a pharmaceutically acceptable diluent therefor.